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The cobalt oxide-vanadium oxide (Co3O4-V2O5) combined with reduced graphene oxide (rGO) having band gap of ∼ 3.3 eV appeared as a suitable photocatalyst for selective oxidation of 2-naphthol to BINOL. C2-symmetric BINOL was achieved with good yield using hydrogen peroxide as the oxidant under UV-light irradiation. The same catalyst was chirally modified with cinchonidine and a newly synthesized chiral Schiff base ligand having a sigma-hole center. The strong interaction of the chiral modifiers with the cobalt-vanadium oxide was truly evident from various spectroscopic studies and DFT calculations. The chirally modified mixed metal oxide transformed the oxidative C C coupling reaction with high enantioselectivity. High enantiomeric excess upto 92 % of R-BINOL was obtained in acetonitrile solvent and hydrogen peroxide as the oxidant. A significant achievement was the formation of S-BINOL in the case of the cinchonidine modified catalyst and R-BINOL with the Schiff base ligand anchored chiral catalyst. The UV-light induced catalytic reaction was found to involve hydroxyl radical as the active reactive species. The spin trapping ESR and fluorescence experiment provided relevant evidence for the formation of such species through photodecomposition of hydrogen peroxide on the catalyst surface. The chiral induction to the resultant product was found to induce through supramolecular interaction like O H…π, H…Br interaction. The presence of sigma hole center was believed to play significant role in naphtholate ion recognition during the catalytic cycle.

Molecular design benefits from a strong partnership between chemical intuition and machine learning. Given the proliferation of machine learning in the small molecule catalyst space, several ideas ...

Cinchona which belongs to family Rubiaceae, got its importance from the centuries because of its anti- malarial activity. Alkaloids present in this herb, Quinine, Chichonine, Quinidine and Cinchonidine are the main, but percentage may vary in species to species. Since the early 17th century, these alkaloid are frequently used in Indian ayurvedic, sidha and traditional folk medicine to treating fever and Still now in modern medicine cinchona alkaloids are used for the treatment of malaria as well as for other diseases and became the well-known drug after the treatment of malaria caused by Plasmodium Sp. Literature study revealed that along with the antimalarial activity the cinchona alkaloids has other potentiality like anti-obesity, anti-cancer, anti-oxidant, anti-inflammatory, anti-microbial activity. These article reviews the biological activities of cinchona alkaloids along with its toxic effect.

A V2O5@TiO2 catalyzed green and efficient protocol for the hydroxylation of boronic acid into phenol has been developed utilizing environmentally benign oxidant hydrogen peroxide. A wide range of electron-donating and the electron-withdrawing group-containing (hetero)aryl boronic acids were transformed into their corresponding phenol. The methodology was also applied successfully to transform various natural and bioactive molecules like tocopherol, amino acids, cinchonidine, vasicinone, menthol, and pharmaceuticals such as ciprofloxacin, ibuprofen, and paracetamol. The other feature of the methodology includes gram scale synthetic applicability, recyclability, and short reaction time.

espanolLa familia Rubiaceae presenta especies que contienen alcaloides en la corteza, raices, hojas, flores, frutos, semillas y polen. Muchas especies del genero Cinchona y Ladenbergia, son fuentes de quina, remedio de origen natural para controlar la malaria. Los objetivos del estudio fueron realizar la caracterizacion taxonomica de Cinchona pubescens y Ladenbergia oblongifolia, cuantificar los alcaloides en hojas mediante cromatografia liquida de alta resolucion (HPLC) y determinar el perfil quimico en muestras de corteza mediante HPLC acoplada a Espectrometria de Masas (LC-MS). Se ha corroborado la clasificacion taxonomica a partir de muestras dendrologicas. Asimismo, se determino presencia de cinchonidina, quinidina y quinina en muestras de hojas de C. pubescens y L. oblongifolia. No se detecto presencia de cinchonina en las muestras evaluadas. Se encontro que un g de muestra de hojas de C. pubescens, contiene 0,64 µg de alcaloide, de las cuales, 0,18 µg corresponden a cinchonidina, 0,40 µg de quinidina y 0,06 µg de quinina. Un g de muestras de hojas de L. oblongifolia, contiene 0,99 µg de alcaloides, de los cuales, 0,24 µg son de cinchonidina, 0,40 µg de quinidina y 0,35 µg de quinina. El contenido de alcaloides totales fue del 0,0064%, del cual, 28,13% es cinchonidina, 62,50% es quininidina y 9,38% es quinina. En la corteza de C. pubescens se ha identificado hasta 55 compuestos entre derivados del acido benzoico, flavonoles, catequinas, antocianinas y triterpenos derivados del acido quinovico. Palabras Claves: Caracterizacion, alcaloides, perfil quimico, Cinchona, Ladenbergia EnglishThe Rubiaceae family has species that contain alkaloids in the bark, roots, leaves, flowers, fruits, seeds and pollen. Many species of the genus Cinchona and Ladenbergia are sources of cinchona, a natural remedy to control malaria. The objectives of the study were to carry out the taxonomic characterization of Cinchona pubescens and Ladenbergia oblongifolia, quantify the alkaloids in leaves using high-performance liquid chromatography (HPLC) and determine the chemical profile in bark samples using HPLC coupled to Mass Spectrometry (LC-MS). The taxonomic classification has been corroborated from dendrological samples. Likewise, the presence of cinchonidine, quinidine and quinine was determined in leaf samples of C. pubescens and L. oblongifolia. The presence of cinchonine was not detected in the evaluated samples. It was found that one g of C. pubescens leaf sample contains 0.64 µg of alkaloid, of which 0.18 µg correspond to cinchonidine, 0.40 µg of quinidine and 0.06 µg of quinine. One g of L. oblongifolia leaf samples contains 0.99 µg of alkaloids, of which 0.24 µg are cinchonidine, 0.40 µg quinidine and 0.35 µg quinine. The content of total alkaloids was 0.0064%, of which 28.13% is cinchonidine, 62.50% is quininidine and 9.38% is quinine. In the cortex of C. pubescens, up to 55 compounds have been identified including benzoic acid derivatives, flavonols, catechins, anthocyanins and triterpenes derived from quinovic acid. Keywords: Characterization, alkaloids, chemical profile, Cinchona, Ladenbergia DOI: http://dx.doi.org/10.17268/rebiol.2020.40.02.11

Heterogeneous enantioselective catalysis is an attractive approach to produce enantiopure chemicals, which are key intermediates for pharmaceutical products. Herein, mesocellular silica foams (MCFs) functionalized by primary, secondary, and tertiary amine groups were used as supports for Pt nanoparticles. The catalytic performances of the Pt/amine-functionalized MCFs were evaluated for the enantioselective hydrogenation of methyl pyruvate in the presence of cinchonidine. Compared to Pt/MCF, the Pt/amine-functionalized MCFs exhibited enhanced activity and enantioselectivity. Particularly, 0.5 wt% Pt/NH 2-MCF showed a superior performance than 5 wt% Pt/Al2O3, a highly efficient catalyst in the enantioselective hydrogenation of α-keto esters, despite a 10 times lower Pt loading. Furthermore, the Pt/NH2-MCF yielded 100% conversion and 96% ee at 0.1 MPa H2 pressure during nine successive cycles, thus showing high reusability. The excellent performance of the Pt/amine-functionalized MCFs is attributed to the formation of electron-deficient Pt species through strong interactions between the Pt nanoparticles and amine groups.

The first iridium-catalyzed enantioselective olefinic C(sp2)–H allylic alkylation is developed in cooperation with Lewis base catalysis. This reaction, catalyzed by cinchonidine and an in situ generated cyclometalated Ir(i)/phosphoramidite complex, makes use of the latent enolate character of an α,β-unsaturated carbonyl compound, namely coumalate ester, to introduce an allyl group at its α-position in a branched-selective manner in moderate to good yield with good to excellent enantioselectivities (up to 98 : 2 er)., The first iridium-catalyzed enantioselective allylic alkylation of an olefinic C(sp2)–H bond – that of an α,β-unsaturated carbonyl compound, is developed in cooperation with Lewis base catalysis.

Pharmaceutical multicomponent crystals (MCCs) including salts and co-crystals of active pharmaceutical ingredients (APIs), are an active focus of research to improve various physicochemical properties of drugs. In this work, we demonstrate that the pharmaceutical artesunate (AS), a derivative of artemisinin (ART), forms a 1 : 1 salt with two cinchona alkaloids: quinine (QN) and cinchonidine (CND), representing the first report of MCCs combining two major types of antimalarial drugs.

Herein, a new type of highly-active platinum (Pt) nanoparticle encapsulated alumina-doped resorcinol–formaldehyde carbon composite (Al@RFC) is fabricated based on resorcinol–formaldehyde (RF) resin and aluminum acetylacetonate using a one-step carbonization approach and evaluated for an asymmetric hydrogenation (AH) reaction. The carbonization process of RF is essentially completed at 700 °C and resulted in Al@RFC with uniform and ordered porous structures. The Pt/Al@RFC catalysts are decorated with uniformly dispersed Pt nanoparticles of around 4 nm diameter over the Al@RFC support. The prepared catalysts are chirally modified with cinchonidine (CD) to explore the catalytic efficiency of AH of ethyl 2-oxo-4-phenylbutanoate (EOPB). The Pt/Al@RFC catalysts have substantially circumvented the shortcomings of poor repeatability of Pt/Al2O3 and low ee values of Pt/C catalysts, displaying conversion efficiencies and ee values of 99% and 82%, respectively. Furthermore, the catalyst could be reused 16 times. Notably, the optimized catalyst displayed turn-over frequency (TOF) values of more than 80 000 h−1, which is the highest reported activity in this hydrogenation reaction. Graphene formation during the high temperature (700 °C) carbonization process is proposed to play a role in its exceptionally high activity.

Coadsorption of hydrogen and cinchonidine (CD), the chiral modifier most frequently applied to bestow chiral sites onto platinum group metals, has been studied theoretically. In focus was the stabi...

Ag–Cu bimetallic nanoparticles were synthesised and used as cathode materials for the asymmetric electroreduction of ethyl benzoylformate. The reaction induced by cinchonidine was conducted in an undivided cell to produce the optically active ethyl mandelate. We obtained ethyl mandelate with 54% enantiomeric excess and 42% yield under the optimal conditions.

The outbreak of SARS-CoV-2 has initiated an exploration to find an efficient anti-viral agent. From the previous scientific studies of traditional herbal medicines like garlic, ginger, onion, turmeric, chilli, cinchona and pepper, 131 chemical constituents were identified. The filtered search of drug-like-molecules searched using Datawarrior resulted in 13 active constituents (apoquinine, catechin, cinchonidine, cinchonine, cuprediene, epicatechin, epiprocurcumenol, epiquinine, procurcumenol, quinidine, quinine, zedoaronediol, procurcumadiol) showed no mutagenic, carcinogenic or toxic properties. In silico study of these 13 compounds with the best binding affinity towards SARS-CoV-2 protease was carried out. The ligands were subjected to molecular docking using Autodock Vina. Epicatechin and apoquine showed highest binding affinity of -7 and -7.5kcal/mol while catechin and epicatechin showed four hydrogen bond interactions. It is interesting and worth noticing the interaction of GLU166 residue with the ligand in most of the constituents. The effectiveness of catechin and epicatechin as an antiviral agent could be tested against COVID-19.

The adsorption from a solution of s-1-(1-naphthyl)ethylamine (s-NEA), cinchonidine, and cinchonine on Pt/SiO2, Pt/Al2O3, and a Pt disk was probed in situ by infrared absorption spectroscopy. Adsorp...

Endeavor to discover biorational natural products-based insecticides, two series (27) of novel 9R/S-acyloxy derivatives of cinchonidine and cinchonine were prepared and assessed for their insectici...

The effects of the quinoline ring modification of cinchonidine (CD) on the enantioselectivity of the asymmetric hydrogenation of (E)-2,3-diphenylpropenoic acid over chirally modified Pd/C were systematically analyzed from the kinetic points of view. The substitutions at the 2′- and/or 6′-positions of the quinoline ring of CD by a methyl, vinyl, n-butyl, or phenyl group decreased enantioselectivity over the whole range of the modifier concentration. Kinetic analysis allowed us to estimate the intrinsic enantioselectivity at modified sites and adsorption strength of the modifier. It is revealed that the substitutions reduce both the intrinsic enantioselectivity and adsorption strength of the parent modifier. The intrinsic enantioselectivity is correlated, most likely, to the modifier–substrate interaction strength.

As a non-covalent interaction of a chiral scaffold in catalysis, pnicogen bonding of epi-cinchonidine (epi-CD), a cinchona alkaloid, was simulated to consider whether the interaction can have the potential controlling enantiotopic face like hydrogen bonding. Among five reactive functional groups in epi-CD, two stable complexes of the hydroxyl group (X-epi-CD1) at C17 and of the quinoline ring (X-epi-CD2) at N16 with pnictide family analytes [X = substituted phosphine (PX), i.e., F, Br, Cl, CF3, CN, HO, NO2, and CH3, and pnictide family analytes, i.e., PBr3, BiI3, SbI3, and AsI3] were predicted with intermolecular interaction energies, charge transfer (QMulliken and QNBO), and band gap energies of HOMO–LUMO (Eg) at the B3LYP/6-31G(d,p) level of density functional theory. It was found that the dominant site of pnicogen bonding in epi-CD is the quinoline ring (N16 atom) rather than the hydroxyl group (O36 atom). In addition, the UV-Vis spectra of the complex were calculated by time-dependent density functional theory (TD-DFT) at the B3LYP/6-31+G(d,p) level and compared with experimental measurements. Through these calculations, two intermolecular interactions (H-bond vs. pnicogen bond) of epi-CD were compared.

In the enantioselecitve hydrogenation of (E)-2-methyl-2-butenoic acid (1) over a cinchonidine-modified Pd/C catalyst, the addition of hydrogen preferentially proceeds from the Re-Si enantioface of ...

Two base-promoted quadruple domino reactions between thioaurones and allylic phosphonium salts have been developed to synthesize benzothiophene-fused oxa[6.6.5]tricyclic skeletons in moderate to good yields with excellent stereoselectivity and broad functional-group tolerance. This is a simple and useful protocol for the rapid construction of the umbrella-like oxa[6.6.5]tricyclic skeleton.

Shape-controlled metal nanocrystals possess the advantages of specific atomic arrangement on the surface and uniform size, which can act as ideal model catalysts for heterogeneous enantioselective catalytic studies. Nevertheless, capping agents are commonly retained on the surface of the as-synthesized metal nanocrystals, which may hinder the necessary interaction between the substrate and the chiral modifiers coadsorbed on the metal surface for chiral recognition. In this paper, we directly synthesized dendritic or cubic palladium nanocrystals in-situ modified by chiral modifiers such as cinchonidine (CD) or S-proline through a one-pot strategy by replacing the conventional capping agents with the chiral modifiers. The as-prepared CD-modified Pd nanodendrite catalyst already exhibits enantioselectivity in the asymmetric hydrogenation of (E)-α-phenylcinnamic acid without subsequent chiral modification processes. The in-situ S-proline-modified Pd nanocube catalyst shows higher enantioselectivity than nanoc...

Herein, we present a new strategy that for the first time achieved chemo- and enantio-selective hydrogenation of alkenes over arylhalides. Key to the success is that instead of using external poisons, we use the composition of the bimetallic nanocrystal catalysts to control chemoselectivity (hydrogenation of C=C bonds without cleavage of Ar-X bonds). We further show that this system combined with surface modifying chiral ligands can control the enantioselectivity. Thus, after synthesizing and screening a series of easily accessible MxAuy (M = Pd, Pt; x, y = 1, 3, 5) bimetallic nanocrystals (9-10 nm) supported on activated carbon, we identified that Pt1Au1/C is a recyclable and generally applicable catalyst for the chemoselective hydrogenation of alkenes without cleaving aryl halogen bonds. Furthermore, cinchonidine modified Pt1Au1/C is shown to be capable of enantioselective hydrogenation, as illustrated by the rapid and enantio-enriched synthesis of RIP1 inhibitor analogue 7-Br-O-Nec1.

Rhodium nanoparticles (Rh NPs) stabilized by natural cinchona alkaloids were synthesized in imidazolium-based ionic liquids using H2 as the reductant. Characterization showed well-dispersed Rh NPs of about 1.96 nm (TEM and HRTEM) and confirmed the ionic liquid and cinchona alkaloid stabilization to the Rh(0) NPs (XPS). When modified by chiral diamine, including (1R,2R)-diphenylethylenediamine ((1R,2R)-DPEN) or cinchona alkaloid derivatives, the Rh NPs catalysts exhibited good activity, chemoselectivity and enantioselectivity in the heterogeneous enantioselective hydrogenation of aromatic ketones. Synergistic effect between (1R,2R)-DPEN and cinchonidine was also observed, which significantly accelerated the reaction rate and enhanced the enantioselectivity. 63.0% enantioselectivity and 98.9% chemoselectivity could be achieved in the acetophenone enantioselective hydrogenation; up to 70.2% enantioselectivity and 100% chemoselectivity was obtained in the isobutyrylbenzene catalytic enantioselective hydrogenation. Catalytic system could be reused several times without significant loss in activity, chemoselectivity as well as enantioselectivity. This catalytic protocol opens the door to heterogeneous enantioselective hydrogenation of aromatic ketones with metal Rh NPs immobilized in ionic liquid.

The preparation of new organocatalysts for asymmetric syntheses has become a key stage of enantioselective catalysis. In particular, the development of new cyclodextrin (CD)-based organocatalysts allowed to perform enantioselective reactions in water and to recycle catalysts. However, only a limited number of organocatalytic moieties and functional groups have been attached to CD scaffolds so far. Cinchona alkaloids are commonly used to catalyze a wide range of enantioselective reactions. Thus, in this study, we report the preparation of new α- and β-CD derivatives monosubstituted with cinchona alkaloids (cinchonine, cinchonidine, quinine and quinidine) on the primary rim through a CuAAC click reaction. Subsequently, permethylated analogs of these cinchona alkaloid–CD derivatives also were synthesized and the catalytic activity of all derivatives was evaluated in several enantioselective reactions, specifically in the asymmetric allylic amination (AAA), which showed a promising enantiomeric excess of up to 75% ee. Furthermore, a new disubstituted α-CD catalyst was prepared as a pure AD regioisomer and also tested in the AAA. Our results indicate that (i) the cinchona alkaloid moiety can be successfully attached to CD scaffolds through a CuAAC reaction, (ii) the permethylated cinchona alkaloid–CD catalysts showed better results than the non-methylated CDs analogues in the AAA reaction, (iii) promising enantiomeric excesses are achieved, and (iv) the disubstituted CD derivatives performed similarly to monosubstituted CDs. Therefore, these new CD derivatives with cinchona alkaloids effectively catalyze asymmetric allylic aminations and have the potential to be successfully applied in other enantioselective reactions.

Pharmacologically mediated reactivation of γ-globin gene with an increase in fetal hemoglobin production, is a cost effective experimental therapeutic intervention for the management of β-hemoglobinopathies. Investigation of new pharmacological agents as HbF inducers from natural resources is desirable to develop safe and effective HbF inducers. We evaluated selected cinchona alkaloids (cinchonidine and quinidine) for their potential of erythroid differentiation and augmentation of fetal hemoglobin production. K562 cells were used as in vitro experimental model. Erythroid differentiation of K562 cells was studied using a benzidine assay, and total hemoglobin was estimated through a calorimetric method. Whereas, quantitative real-time PCR (qRT-PCR) was used to analyse γ-globin gene expression, and flow cytometry and immunofluorescence microscopy for evaluating HbF production. Cinchona alkaloids showed dose dependent erythroid differentiation, time driven cellular proliferation, with kinetics of hemoglobin accumulation in K562 cells. The findings of qRT-PCR showed an increase in expression of γ-globin mRNA content (3.17-fold in cinchonidine and 2.03-fold increase in quinidine treated K562 cells), accompanied by an increase in fetal hemoglobin production. Altogether, this study demonstrates that cinchona alkaloids can be used as therapeutic agents in treating β-thalassemia after further biological investigation.

Trajectory analysis can provide information on the complete conformational or configurational space of molecular systems and their reactivity. Numerical analysis of trajectories can be performed in any type of coordinate system, e.g. Cartesian coordinate system, internal or normal coordinates, etc. In some applications, various coordinate systems will hold redundant information due to the linear dependence. A set of molecular coordinates contains null-vectors that introduce numerical instabilities and noise in the processing. In the case of a larger number of defined coordinates, there is also a problem with storage and data processing. In this work, the procedure for constructing generalized and linearly independent set of internal molecular coordinates will be evaluated. Generalized internal coordinates are chemically intuitive and can be defined in a number of ways, for example: distances, angles or dihedral angles. By applying machine learning to molecular dynamics trajectory, a complete and linearly dependent set of generalized internal coordinate distances will be reduced to the linearly independent set that still contains all relevant information about conformational or configurational space, reactivity and molecular motion. Given procedure will be applied to the molecule of (R)-cinchonidine. Analiza trajektorije može pružiti informacije o potpunom konformacijskom ili konfiguracijskom prostoru molekularnih sustava i njihovoj reaktivnosti. Numerička analiza trajektorija može se provesti u bilo kojem koordinatnom sustavu, npr. Cartesiusov koordinatni sustav, sustav internih ili normalnih koordinata, itd. No, u nekim aplikacijama različiti koordinatni sustavi zadržavaju suvišne informacije zbog linearne zavisnosti. Taj skup molekularnih koordinata sadrži nul-vektore koji onda uzrokuju numeričke nestabilnosti i numerički šum. U slučaju većeg broja definiranih koordinata također postoji i problem s pohranom te obradom podataka. U ovom će se radu razraditi postupak za kreiranje generaliziranog i linearno nezavisnog skupa internih koordinata. Generalizirane interne koordinate kemijski su intuitivne, a mogu se definirati na više načina, na primjer: međuatomne udaljenosti, kutovi ili diedarski kutovi. Primjenom strojnog učenja na trajektoriju molekularne dinamike, potpun i linearno zavisan skup generaliziranih internih koordinata međuatomnih udaljenosti reducirat će se na linearno nezavisan skup, ali skup koji još uvijek sadrži sve relevantne informacije o konformacijskom ili konfiguracijskom prostoru, reaktivnosti i gibanju molekula. Razrađeni postupak primijenit će se na molekulu (R)-cinhonidina.

International audience; Cinchonidine-functionalized β-cyclodextrin was used as stabilizing agent for platinum nanoparticles dispersed in water, but also as chiral modifier for the asymmetric hydrogenation of ethyl pyruvate at 30 °C under 40 bar of hydrogen. This functionalized cyclodextrin allowed getting more stable, more catalytically active and also more enantioselective Pt nanoparticles compared to control catalytic systems. NMR and MALDI-MS analyses clearly showed the reduction of the vinyl group of the cinchonidine graft during the nanoparticles preparation. Under hydrogen pressure, the hydrogenation of the quinolinic moiety was also proven and can be responsible for the difficulties encountered during the recycling study.

A small family of novel modular monofunctional epicinchonidine-1,2,3-triazole compounds was prepared in very good overall yield (3 steps from cinchonidine, 49���87% yield) using simple Cu(I) catalyzed click-chemistry. The objective of this study was to access their hitherto unknown catalytic role in some key organic reactions like: ketimine hydrosilylation, Michael-addition and the Biginelli reaction. This is the first report on the application of cinchonidine derived 1,2,3-triazoles in organocatalysis, and includes catalytic screening and preliminary Density Functional Theory (DFT) mechanistic studies. The new compounds were screened for antimalarial activity against Plasmodium falciparum (W2 strain), exhibiting IC50 values in the range 2.0���6.8 ��M; and cholinesterase inhibition, showing activity against eqBuChE, but their main potential is for tumor anti-proliferation (showing a lowest GI50 of 8.1 ��M). Gratifyingly, all our compounds were non-cytotoxic against the non-tumor healthy cell line, BJ-hTERT and they presented excellent simulated pharmacological properties.

Bacterial infections that do not respond to current treatments are increasing, thus there is a need for the development of new antibiotics. Series of 20 N-substituted quaternary salts of cinchonidine (CD) and their quasi-enantiomer cinchonine (CN) were prepared and their antimicrobial activity was assessed against a diverse panel of Gram-positive and Gram-negative bacteria. All tested compounds showed good antimicrobial potential (minimum inhibitory concentration (MIC) values 1.56 to 125.00 μg/mL), proved to be nontoxic to different human cell lines, and did not influence the production of reactive oxygen species (ROS). Seven compounds showed very strong bioactivity against some of the tested Gram-negative bacteria (MIC for E. coli and K. pneumoniae 6.25 μg/mL, MIC for P. aeruginosa 1.56 μg/mL). To establish a connection between antimicrobial data and potential energy surfaces (PES) of the compounds, activity/PES models using principal components of the disc diffusion assay and MIC and data towards PES data were built. An extensive machine learning procedure for the generation and cross-validation of multivariate linear regression models with a linear combination of original variables as well as their higher-order polynomial terms was performed. The best possible models with predicted R2(CD derivatives) = 0.9979 and R2(CN derivatives) = 0.9873 were established and presented. This activity/PES model can be used for accurate prediction of activities for new compounds based solely on their potential energy surfaces, which will enable wider screening and guided search for new potential leads. Based on the obtained results, N-quaternary derivatives of Cinchona alkaloids proved to be an excellent scaffold for further optimization of novel antibiotic species.

Pripravljena je knjižnica od 72 derivata kvazienantiomera cinhonidina i cinhonina. Redukcijom vinilne skupine pripravljeni su 10,11-dihidrocinhonidin i 10,11-dihidrocinhonin koji su iskorišteni zajedno s cinhonidinom i cinhoninom za sintezu N-kvaternih derivata (ukupno 58 spojeva). Nadalje, pripravljeni su monosupstituirani (N-etil, N-cikloheksil i N-fenil) i disupstituirani (N,N-dimetil, N,N-dietil i N,N-difenil) C9 karbamati (serija od 10 spojeva). Oksidacijom C9 hidroksilne skupine pripravljen je keton koji je preveden u ketoksim i kvaterniziran u N-metilni i N-benzilni derivat. Svim pripravljenim spojevima od kojih 22 do sada nisu opisani u literaturi, struktura je dokazana standardnim analitičkim metodama, a primijenjena je spektroskopija nuklearne magnetske rezonancije za studij konformera spojeva u otopini. Testirani derivati pokazali su umjeren do snažan antibiotski potencijal na reprezentativnom panelu Gram-pozitivnih i Gram-negativnih bakterija te su identificirani derivati s inhibicijskim potencijalom prema kolinesterazama. Spojevi odabrani za testiranje nisu pokazali toksičan utjecaj na proliferaciju HEK 293T i HeLa staničnih linija. A library of 72 derivatives of quasienantiomers cinchonidine and cinchonine was prepared. Reduction of vinyl group resulted in 10, 11-dihydrocinchonidine and 10, 11-dihydrocinchonine which were used together with cinchonidine and cinchonine as starting material for the preparation of N-quaternary derivatives (total of 58 compounds). Furthermore, monosubstituted (N-ethyl, N-phenyl and N-cyclohexyl) and disubstituted (N,N-dimethyl, N,N-diethyl and N,N-diphenyl) C9-carbamates were prepared (total of 10 compounds). Oxidation of C9-hydroxyl group yielded a ketone which was further converted to ketoxime and quaternized into N-methyl and N-benzyl derivatives. For all prepared compounds, 22 of which have not been described in the literature so far, the structure was determined by standard analytical methods. Nuclear magnetic resonance spectroscopy was applied to study the conformers of the compounds in solution. The tested derivatives showed moderate to strong antibiotic potential on a representative panel of Gram-positive and Gram-negative bacteria, and derivatives with cholinesterase inhibitory potential were identified. Selected compounds showed no toxic effect on the proliferation of HEK 293T and HeLa cell lines.

Ovim diplomskim radom pripravljen je 10,11-dihidrocinhonidin, njegovi karbamatni derivati te karbamatni derivati cinhonidina. 10, 11-dihidrocinhonidin pripravljen je redukcijom vinilne skupine cinhonidina korištenjem amonijevog formijata i ugljika na paladiju reakcijom prijenosnog katalitičkog hidrogeniranja. Serija karbamatnih derivata pripravljena je reakcijom alkaloida i odgovarajućeg izocijanata ili karbamoil-klorida. Korišteni su fenil- i cikloheksilizocijanat kao i dietil-, difenil- i dimetilkarbamoil-klorid. Dobiveni su mono- i disupstituirani alifatski te mono- i disupstituirani aromatski karbamatni derivati cinhonidina i 10,11-dihidrocinhonidina. Pripravljenim spojevima određeno je specifično optičko zakretanje i talište, a karakterizirani su infracrvenom spektroskopijom te spektroskopijom nuklearne magnetske rezonancije (1H i 13C). In this diploma thesis synthesis of 10,11-dihydrocinchonidine, its carbamate derivatives and carbamate derivatives of cinchonidine was described. 10,11-dihydrocinchonidine was prepared by a transfer catalytic hydrogenation of cinchonidine over a palladium on carbon catalyst using ammonium formate as hydrogen donor. A series of carbamate derivatives was prepared in reaction of an alkaloid and the corresponding isocyanate or carbamoyl chloride. Phenyl- and cyclohexyl- isocyanate were used as well as diethyl-, diphenyl- and dimethylcarbamoyl chloride. Mono- and disubstituted aliphatic and mono- and disubstituted aromatic cinchonidine carbamates and 10,11-dihydrocinchonidine carbamates have been obtained. Optical rotation and melting point of synthesized compounds were determined. Furthermore, synthesized compounds were analyzed by infrared and nuclear magnetic resonance spectroscopy (1H and 13C).

The reaction mechanism and origin of asymmetric induction for conjugate addition of cyanide to the C=C bond of olefin were investigated at the B3LYP-D3(BJ)/6-31+G**//B3LYP-D3(BJ)/6-31G**(SMD, toluene) theoretical level. The release of HCN from the reaction of ethyl cyanoformate (CNCOOEt) and isopropanol (HOiPr) was catalyzed by cinchona alkaloid catalyst. The cyanation reaction of olefin proceeded through a two-step mechanism, in which the C-C bond construction was followed by H-transfer to generate a cyanide adduct. For non-catalytic reaction, the activation barrier for the rate-determining C-H bond construction step was 34.2 kcal mol&minus, 1, via a four-membered transition state. The self-assembly Ti(IV)-catalyst from tetraisopropyl titanate, (R)-3,3&prime, disubstituted biphenol, and cinchonidine accelerated the addition of cyanide to the C=C double bond by a dual activation process, in which titanium cation acted as a Lewis acid to activate the olefin and HNC was orientated by hydrogen bonding. The steric repulsion between the 9-phenanthryl at the 3,3&prime, position in the biphenol ligand and the Ph group in olefin raised the Pauli energy (&Delta, E&ne, Pauli) of reacting fragments at the re-face attack transition state, leading to the predominant R-product.

Among all the malaria parasites, P. falciparum is the most predominant species which has developed drug resistance against most of the commercial anti-malarial drugs. Thus, finding a new molecule for the inhibition of enzymes of P. falciparum is the pharmacological challenge in present era. Herein, ten novel molecules have been designed with an amalgamation of cinchonidine, carbohydrate moiety and triazole ring by utilizing copper-catalyzed click reaction of cinchonidine-derived azide and clickable glycosyl alkynes. The molecular docking of developed molecules showed promising results for plasmepsin inhibition in the form of effective binding with target proteins.

PH46A is a single enantiomer and a member of the 1,2-indane dimer family. It has two contiguous stereogenic centers with S,S configurations, one of which being a quaternary center, which has been developed as a clinical candidate for the treatment of inflammatory and autoimmune conditions. The current synthetic route to PH46A involves the generation of an unwanted enantiomer (R,R)-7, thus reducing the final yield significantly. Therefore, we have investigated potential alternatives to improve the efficiency of this synthesis. The first phase of the study has demonstrated proof of principle for a chiral alkylation of ketone 3 using phase-transfer catalysis, providing a key intermediate ketone (S)-4. The parent alkaloids required for the synthesis of PH46A, quinine or cinchonidine, have also been identified. Promising enantiomeric excesses of up to 50% have been achieved to date, and the use of an alternative substrate, unsaturated ketone 9, has also opened up further avenues for optimisation in future studies. The second part of the study involved preliminary screening the effects of a panel of hydrolase enzymes on (rac)-4 in order to identify a potential chemo-enzymatic route to optimise the introduction of chirality into PH46A at early stage of the synthesis. The hydrolase module has also yielded positive results, enzyme AH-46 with MtBE providing a selectivity factor of 8.4 with enantiomeric excess of 77%. Overall, positive results were obtained in this proof of concept study described herein. It is believed that conditions of both chiral PTC alkylation and biocatalytic hydrolysis could be optimised to further enhance the selectivity and improve the overall yield. This work is currently ongoing.

New efficient catalysts based on electrophilic N-fluoro quaternary ammonium salts are reported for catalytic allylation of (E)-N,1-diphenylmethanimine. The chiral version of the catalyst based on cinchonidine (F-CD-BF4 ) shows high catalytic activity with approximately 94% ee and TOF (>800 h-1 ). The F-CD-BF4 is prepared from cinchonidine and Selectfluor by one-step transfer fluorination.

1H NMR and 13C NMR chemical shifts as well as conformation dependent vicinal 1H–1H spin–spin coupling constants for cinchonidine in a dilute C6D12 solution have been measured. These data have been ...

An organocatalytic enantioselective allylic alkylation of 5H-oxazol-4-ones with Morita-Baylis-Hillman carbonates has been developed. With 10 mol% of commercially available cinchonidine, a wide range of substituted 5H-oxazol-4-one derivatives were constructed in good-to-excellent yields with high diastereo- and enantioselectivities. The allylic alkylation adducts obtained are valuable precursors for the synthesis of chiral α-alkyl α-hydroxycarboxylic acid derivatives, which represent a series of versatile building blocks in many biologically active compounds.

Chinoline alkaloids found in Cinchona bark still play an important role in medicine, for example as antimalarial and antiarrhythmic drugs. For the first time Supercritical Fluid Chromatography has been utilized for their separation. Six respective derivatives (dihydroquinidine, dihydroquinine, quinidine, quinine, cinchonine and cinchonidine) could be resolved in less than 7 min, and three of them quantified in crude plant extracts. The optimum stationary phase showed to be an Acquity UPC2 Torus DEA 1.7 μm column, the mobile phase comprised of CO2, acetonitrile, methanol and diethylamine. Method validation confirmed that the procedure is selective, accurate (recovery rates from 97.2% to 103.7%), precise (intra-day ≤2.2%, inter-day ≤3.0%) and linear (R2 ≥ 0.999); at 275 nm the observed detection limits were always below 2.5 μg/ml. In all of the samples analyzed cinchonine dominated (1.87%–2.30%), followed by quinine and cinchonidine. Their total content ranged from 4.75% to 5.20%. These values are in good agreement with published data, so that due to unmatched speed and environmental friendly character SFC is definitely an excellent alternative for the analysis of these important natural products.

Several synthetic strategies were developed for the preparation of chiral dendrimer-encapsulated Pt nanoparticle (Pt DEN) catalysts. In one approach, regular OH-terminated polyamidoamine (PAMAM) dendrimers were first derivatized with cinchonidine using “click” chemistry and sebacic acid as a linker. As many as half of the 64 terminal OH groups in a 4th generation PAMAM dendrimer could be modified this way, and the overall cinchonidine content could be tuned by controlling the CD:PAMAM ratio during synthesis. Platinum nanoparticles were then added to these cinchonidine-modified dendrimers. In an alternative route, regular Pt DENs were made first using PAMAM, and the resulting material was then derivatized with cinchonidine. The two synthetic routes proved successful, but led to materials with different spectroscopic and catalytic properties, presumably because the metal nanoparticles in the first case are made near the cinchonidine functionality, in the outside of the dendrimer structure rather than in its inside, as believed to be the case with the second procedure. A potential complication related to the poisoning of the Pt nanoparticle surface during synthesis was also identified in the second protocol. The catalytic performance of these catalysts for the hydrogenation of α-ketoesters proved to be poor in all cases, presumably because of a number of problems associated with mass transport limitations inside the dendrimer structures and restricted flexibility of the outer chiral branches, which may not be able to interact with the catalytic surfaces. Nevertheless, interesting synthetic lessons were derived from our work with potential value for other applications.

The purpose of this study was to develop a novel, simple and precise ligand-exchange capillary electrophoresis method to separate the diastereomer pairs of four major cinchona alkaloids (quinine/quinidine and cinchonine/cinchonidine). The l-lysine and copper(II) were chosen as the ligand and the central ion, respectively. Optimal separation conditions of four alkaloids were 4.0 mM l-lys, 2.0 mM copper(II) and 30 mM NH4Ac at pH 8.9 and a applied voltage of 15 kV . Meanwhile, the first-order derivative electropherogram was used for resolving the overlapping peaks of cinchonidine and quinidine. Under the optimum condition, good linearities were obtained with correlation coefficients from 0.9908 to 0.9935. The limits of detection (LOD, S/N = 3) and the limits of quantitation (LOQ, S/N = 10) ranged from 0.24 to 0.41 μg/mL and from 0.73 to 1.35 μg/mL, respectively. The recoveries ranged between 95.38 and 106.03%. The proposed ligand-exchange capillary electrophoresis method was suitable for the quantitative determination of four cinchona alkaloids in some preparations such as Compound Quinine Injection, Tonic Water and Klorane quinine and Vitamin B complex Shampoo.

Hydrogenation of acetophenone and esters of ketoacids with molecular hydrogen in the presence of the Pd(acac)2–(–)-cinchonidine–H2 catalytic system has been studied. The dependence of the molar ratio of (–)-cinchonidine/Pd on size and shape of palladium nanoparticles, formed in the system, also on reaction rate and enantioselectivity has been established. The nature of the regularities observed for the Pd(acac)2–(–)-cinchonidine–H2 catalytic system was discussed.

An organocatalytic asymmetric cascade reaction has been developed for the synthesis of highly substituted pyrrolidines having a stereogenic quaternary centre at the 3-position. N-Tosyl aminomethyl enone and trans-α-cyano-α,β-unsaturated ketone were utilized as the reaction partners in this method. Cinchonidine derived bifunctional amino-squaramide catalysts were the best to obtain the products in high enantio- and diastereoselectivities.

Cinchonidine and Theophylline vitrification abilities have been investigated by differential and fast scanning calorimetry. These active pharmaceutical compounds are known in the literature to have a very high tendency to crystallize which has been confirmed by classical differential scanning calorimetry. Due to the growing interest in amorphous pharmaceutical compounds, their possible vitrifications have been investigated by fast scanning calorimetry. This work shows the high potential of this advanced thermal analysis technique to investigate the vitrification of active pharmaceutical compounds by melt-quenching protocol. For the first time, glass transitions of Cinchonidine and Theophylline were measured. From Cinchonidine, it has been shown that complete glassy state can be obtained by cooling from the melt at 2000K/s. Crystallization has also been suppressed by cooling down from the melt at 2K/s. However, such rate does not avoid the formation of nuclei. Theophylline crystallization process has been suppressed by a melt-quenching protocol carried out with a cooling rate of 4000K/s. However, the phenomenon of nuclei formation upon cooling seems unavoidable at this cooling rate. For both active pharmaceutical compounds, physical aging has been observed to play a role on the nuclei formation below the glass transition leading to modify the subsequent crystallization.

Palladium nanoparticles (PdNPs) prepared in neat glycerol containing TPPTS (tris(3-sulfophenyl)phosphine trisodium salt) or cinchona-based alkaloids (cinchonidine, quinidine) as capping agents, were applied as catalysts in fluoride-free Hiyama couplings and conjugate additions with the aim of evaluating the influence of the stabilizer in the catalytic reactivity. Therefore, PdNPs stabilized by phosphine favored C C cross-couplings, whereas those containing alkaloids showed enhanced suitability for C C homo-couplings and conjugate additions. The metal/stabilizer coordination mode, i.e. Pd P dative bond and π-π interaction between quinoline moiety and palladium surface, is certainly key for the stabilization of different active metallic species and then promoting distinctive catalytic pathways.

The novel base-catalyzed stereoselective intramolecular dearomatizative [4+2] cycloaddition of o-phenylene-linked ethynylnaphthol-benzofuran systems is described. In this reaction, we presume the involvement of electrophilic vinylidene o-quinone methides (4π), which adds across the electron-rich furan double bonds (2π), producing elaborate fused oxa-polyheterocyclic frameworks with consecutive quaternary and tertiary asymmetric carbon atoms as single diastereomers. The catalytic and enantioselective synthesis of this chiral fused polyheterocyclic structure is also feasible using a prevalent chiral base: cinchonidine and cinchonine.

Pt nanoparticles supported on three-dimensionally ordered macroporous carbon (Pt/3DC) were prepared and applied as catalyst after chirally modified with cinchonidine for the enantioselective hydrogenation of ethyl pyruvate. The catalyst was characterized by SEM, TEM, powder XRD, N 2 sorption, and CO chemisorption, which confirmed the well-defined periodic macroporous structure of Pt/3DC and the high dispersion of Pt nanoparticles on the support. High catalytic performance was achieved over chirally modified Pt/3DC catalyst in the asymmetric hydrogenation of ethyl pyruvate. A high turnover frequency of 11,800 h −1 with an enantiomeric excess of 79.5% was acquired in acetic acid. In particular, this catalyst exhibited high durability in the asymmetric hydrogenation system and could be easily reused at least 13 times with well-maintained catalytic activity and slightly decreased enantioselectivity. Moreover, the comparison of catalytic performance between Pt/3DC and commercial Pt/C as well as Pt/Al 2 O 3 was carried out.

Myrtucommulones belong to a class of pharmacologically active natural compounds which offer various alternatives to the treatment of pain, inflammation and cancer. Their stereoselective synthesis remains therefore a key-challenge towards its use in the pharmaceutical industry. In the present work myrtucommulone A and B were synthesised through metal catalysis with 81 and 72% ee respectively. Thanks to the use of cinchonidine as an organocatalyst, 82 and 84% de were reached for myrtucommulone A and myrtucommulone F respectively. Simultaneously, a new synthetic method emerged and gave access to new range of possibilities for the preparation of myrtucommulone derivatives under mild conditions or through a one-pot reaction.

Mizoroki–Heck (MH) polymerization of cinchonidine-based sulfonamide dimers produces polymers containing a chiral sulfonamide moiety in each repeat unit. Quinidine sulfonamides are known to have excellent catalytic activity in the asymmetric Michael addition reaction of β-ketoester and nitrostyrene. We found that cinchonidine sulfonamides used as bifunctional chiral catalysts showed even higher stereoselectivity in the same reaction. The polymers synthesized by MH polymerization also showed high levels of diastereo- and enantioselectivity (up to 99% enantiomeric excess) in the reaction. Owing to the insolubility of the polymeric catalysts, they were separated easily from the reaction mixture and reused several times without any loss of catalytic activity.

A one-step approach was developed to prepare carbon covered alumina (CCA) material by using Al-based MOFs (Al-PCP) as sacrificial template. Pt/CCA nanoparticle catalysts were characterized by using XRD, TGA, XPS, N 2 sorption, SEM, TEM and elemental analysis and revealed that they retained the mesostructure with high Pt dispersion and had a CCA structure. Moreover, after reduced at 800 °C, Pt/CCA-800 afforded the highest enantiomeric excess (84.8%) after chirally modified with cinchonidine at the second time reaction and can be recycled for more than 8 times without distinct loss of activity or enantioselectivity in the asymmetric hydrogenation of ethyl 2-oxo-4-phenylbutyrate.

Efficiency of palladium solid supported (Pd/SS) catalysts for one-step isomerisation of the side chain of four natural Cinchona alkaloids have been explored under controlled microwave heating in the green media (50% aqueous ethanol or ethylene glycol with HCl). Conversion progress and products purity was monitored by TLC and by 1H NMR spectrometry. Final conversion is dependent on the support (Al2O3, C or BaSO4), reaction time and temperature. Very good results: high yields and purity of (Z/E) Δ3,10-isomers were obtained from quinine and quinidine with 10% Pd/BaSO4 as the catalyst, which is less effective for isomerisation of cinchonine and cinchonidine. Enhancing energy efficiency can be possible when the responsive support selective absorbs of microwave energy, which is translated to the palladium giving acceleration of the formation and disintegration of the transition state leading to Δ3,10-isomers.

A new class of thioamide-substituted cinchona derivatives is reported. A convergent and practical approach was developed to insert the thioamide functional group onto the cinchonidine from readily available dithioesters. These organocatalysts were effective in asymmetric decarboxylative Mannich and protonation reactions of alpha-amido-substituted Malonic Acid Half Oxyesters (MAHOs) affording alpha,beta- and alpha-amino acid derivatives in good yields and stereoselectivities respectively.

This research was aimed to synthesize cinchonidine isobutyrate ester and conduct a preliminary assay for anticancer agent using cytotoxicity assay to Artemia salina Leach larva, or also known as brine shrimp lethality test (BSLT). Cinchonidine, a compound that has quinoline rings and quiniclidine ring, is a quinine analogue and stereoisomer of cinchonine. Cinchonidine is predicted to have anticancer activity. Synthesized ester was aimed to gain higher lipophilicity. Higher lipophilicity makes it easier for the compund to pass through cell membrane. The esterification process used DMAP as a catalyst, DCC as an activator, and isobutyric acid as a carboxilyc acid. Isobutyric acid is a type of short chained fatty acid that usually acts as an anticancer prodrugs. The product is identified by ESI-MS, FT-IR, 1H-NMR, dan 13C-NMR. Ester cinchonidine isobutyrate is gelatinous and colourless with yield of 21,77%. BSLT result showed that cinchonidine isobutyrate ester had LC50 value of 75.16 ppm which was more toxic than cinchonidine that had LC50 value of 99.2 ppm. It was proved that higher lipophilicity could increase pharmacology activity